Last night, I headed down to the beautiful Bell House, in the Gowanus section of Brooklyn, for this month's Secret Science Club lecture, featuring structural biologist Dr Kevin Gardner, Einstein Professor of Chemistry & Biochemistry at City College of New York Director of the Structural Biology Initiative at CUNY’s Advanced Science Research Center. Dr Gardner titled his lecture Harnessing Nature's Switches: Discovering New Biotech Tools and Drug Targets.
Dr Gardner began the lecture with a question- how do cells 'listen' to the world around them and act on that information? Cells have to respond to outside stimuli second to second, minute to minute. Figuring out these mechanisms is important to biomedical research. Cells have the ability to sense oxygen levels in order to respond to conditions of hypoxia. Plant cells have to sense light levels so they can discontinue photosynthesis after sundown. Fish have the ability to sense pollutants in water, with the sensitivity callibrated to pollution levels. These cellular 'switches' are variants of the same basic process, which involves small molecules, such as the protein rhodopsin (derived from vitamin A). The switches get proteins to change shape in response to stimuli.
Dr Gardner told us the mantra of structural biology: Structure Determines Function. Biology can be likened to the opposite of architecture... in biology, structure determines function, while in architecture, function determines structure. An architect tasked to design a concert hall will base the structure on the acoustic needs of performances. With biologists, evolution is the 'client'. Biology has produced some good structures, but a lot of okay structures.
In the 1950s, the structure of DNA was determined, creating the models involved a lot of chemistry. Around the same time, the role of proteins such as myoglobin and hemoglobin was being studied. New insights into disease, such as the role of a single point mutation in sickle-cell anemia, were being made. Dr Gardner then took a moment to recognize the role of graduate students, who do most of the work in scientific research.
Dr Gardner then stated the multi-disciplinary nature of structural biology- structural biologists answer biology's questions, harness chemistry's intuition, and use physics' tools. In order to view the small molecules used in cellular switches, electron microscopes are needed. A typical human cell is ten to thirty microns in diameter. Images of cells must be 'blown up' to allow researchers to 'look around'. Using the example of a myoglobin molecule, Dr Gardner noted that, if a cell were blown up to the size of One World Trade Center, a myoglobin molecule inside it would be an inch in diameter.
Dr Gardner then described the various instruments of his trade (the 'tools of physics') in dramatic terms. He joked that they constituted 'science built on a dare'. Cryoelectron microscopes use extremely low temperatures to reduce damage to biological specimens, allowing 3D images to be obtained (Dr Gardner quipped, "Don't mess around with electron guns"). Nuclear magnetic spectroscopy (Dr Gardner noted wryly, "Anything nuclear is good") involves using a large 'Thermos' with liquid nitrogen and liquid helium chambers wrapped with thousands of feet of superconductor cables, and utilizes a localized magnetic field millions of times more powerful than that of the Earth to obtain images of proteins- Dr Gardner described it as 'an atomic MRI'. A more 'sane' method of imaging molecules is X-ray crystallography, in which molecules in rows in a crystal have x-rays shone through them- the x-ray being intense enough to set air on fire. Again, Dr Gardner joked that this was 'science built on a dare'.
After this overview of imaging methodology, Dr Gardner got to the core subject of his lecture, beginning with an introduction to G Protein-Coupled Receptors, which are found in cell membranes and trigger cellular responses to outside molecules. GRCRs are the target of two-thirds of all pharmaceuticals- the drugs hijack GPCRs to result in a clinical outcome. Rhodopsin is a GPCR found in the human retina. Protein domains are pieces of protein, and Per-Arnt-Sim (PAS) domains are the protein pieces that act as molecular sensors. Three PAS domains were identified in 1991, and there are currently about forty-thousand known PAS domains.
Light-oxygen-voltage-sensing (LOV)domains are PAS domains which detect blue light, they can be turned on or off by shining blue light on them. LOV domains contain a derivative of riboflavin. They convert blue light into biochemical signals which are also dependent on other factors. One of the processes controlled by LOV factors is phototropism, the movement of plants toward light sources. If the PAS domain regulating the sensing of blue light can be knocked out, no phototropism occurs. In plants, the 2LOV domain activates a kinase which triggers the response. In darkness, the flavins are bound covalently, blue light creates new bonds to turn on the kinase. After checking with Dorian and Margaret that the Bell House crowd was over 21, Dr Gardner declared this process 'batshit crazy'. Blue light synchronizes the switches, which shut down after sundown. Rhodopsin in animal eyes shuts down images rapidly, so they don't persist, but plants don't need quick reaction times, so the light-detection-and-reaction process is slower than that of animals... Dr Gardner describe it as a 'good enough' evolutionary solution. Laser equipped NMR spectrometers can be used to study phototropics such as LOV2, which covert changes in light into changes in activity.
Besides studying PAS domains in the lab, biologists sequence DNA from a variety of organisms in order to identify proteins. Dr Gardner cited the 1KP Project, which sequenced the genomes of 1,100 plant species. This is being followed up with the even more expansive 10KP Project. Dr Gardner described a 'bioinformatics pipeline' from the field to the lab, and quipped that 'Nature's been busy'. He also stated another scientific mantra: MODELS GOOD, DATA BETTER.
He took a brief moment to express some envy of the scientists working in the field... he's a recreational diver, but the oceanic data has been outsourced to other researchers. He has, though, done field work in a local swamp. Using this as a transition, he then brought up the subject of the bacterium Erythrobacter litoralis, the genome of which was sequenced from a specimen collected in the Sargasso Sea. This bacterium is an opportunist, it can use photosynthesis to provide energy. Dr Gardner explained the significance of blue light- it penetrates deeper into seawater than other wavelengths. Erythrobacter litoralis has sensors which check light levels, which are dependent on both time and depth. A light-activated binding protein (EL222) was discovered in Erythrobacter litoralis, light 'flips the switch' to turn genes on. Other blue light sensing proteins are also known. Dr Gardner posed the question, are these 'bacteria only' tricks, or do eukaryotes use them? LOV PAS domains have been found in fungi such as brewers' yeast. Detection methods used to examine to action of photosensory and binding domains, and the changes in shape caused by exposure to light are not friendly to living organisms. To study these proteins, researches set beacons in the domains, flash them, and measure the changes. Because the LOV domains respond to blue light, these researches work, like Roxanne, under red light.
Dr Gardner told us to keep our eyes on optogenetics for an upcoming Nobel Prize. Place genes in organisms and use novel ways to illuminate them. Dr Gardner showed a video (which I haven't been able to locate yet) of a rat which had had an algal gene inserted into it using a virus, and a fiber optic cable inserted into its brain so neurons could be turned on or off using lasers, resulting in behavioral changes, in this case, feeding. After this look at one class of algal photoreceptors, researchers can go on to other photoreceptors, of which thirteen classes are known, detecting light from the ultraviolet to the infrared. Putting bacterial receptors into eukaryotes poses some issues- the receptors have to deal with the presence of a cell nucleus and 'figure out' the mechanisms of the eukaryotic cell. The EL222 protein has been turned into a research tool, inserted into organisms such as mice, yeast, and zebrafish. The more the gene expression in an organism, the more the response to light. The proteins which 'see light' in plants bond to other proteins and change their shape have been turned into biotech tools.
After this introduction to light sensors, Dr Gardner shifted to the subject of hypoxia sensors, the subject of the 2019 Nobel Prize in Physiology and Medicine. Hypoxia-inducible factor 1-alpha (HIF1A) is a PAS domain made in cells. HIFA1 is destroyed in real-time under normal conditions. If not enough oxygen is present, HIFA1 is not destroyed, which set up a response to produce more ATP (the fuel of the cell), and animals produce more red blood cells are reroute blood circulation to oxygen-starved body parts. HIFA1 can be used to treat anemia or blood circulation problems, but it also has the potential to be used for 'doping' by endurance athletes. Dr Gardner ruefully noted that speed walkers had beaten cyclists to the punch when it came to doping using a drug which inhibits HIFA1 destruction. Genes are turned on when they are needed. The genetic factors which produce growth can promote unregulated growth, cancer. If the system is broken, it is possible that shutting down HIFA1 production in cells can inhibit cancer. The structure of HIFA1 is similar to the structure of phototropic PAS domains.
Dr Gardner finished up with an exploration of biomedical research. One ongoing project is the building of 'libraries' of chemicals which could potentially be the 'grandfathers' of medicines. Fragment-based drug discovery involves observing where various chemicals bond, to which proteins. Currently, two-hundred thousand compounds are being testing for their potential as medicines. Do the compounds bond? Do the compounds do something functional? So far, eighty-five compounds merit further testing. He himself was involved with a small company, Peloton Therapeutics, which evaluated an HIF inhibitor (PT399) which might be used to treat kidney cancer, and is now in clinical trials. Peloton Therapeutics was bought by Merck. Dr Gardner noted that while plants and humans have different biology, they have similar regulation- plant work was what got us to bacterial work which got us to work on humans. He also reminded us that the biologists couldn't have gotten to this stage without physics and chemistry. Research is expensive, but drug costs are high for non-academic reasons... small companies take on the drug discovery risks and get bought out by pharmaceutical giants when they become established. Dr Gardner ended the lecture by thanking all of his grad students, and suggested that the audience buy these good people a drink in gratitude.
The lecture was followed by a brief Q&A session. Some Bastard in the audience asked the good doctor if current models proposed a single origin for blue light sensing protein domains, or if they evolved multiple times in different lineages, was it divergent or convergent evolution? Dr Gardner stated that there is good genetic evidence that blue light sensors are all derived from a common ancestor. Another questioner asked about circadian rhythms- even fungi such as bread mold have cues for timing. Light and feeding tend to correlate. Another question involved (I'd love to know what inspired this) the role that oxygen sensors might play in the incidence of obesity in high-altitude populations. Dr Gardner noted that populations in the Himalayas and Andes have evolved various HIF-related ways (more than one) to solve altitude issues. In the Himalayas, specifically Tibet, there are mechanisms which turn down HIF domains to prevent overly thickening the blood with red blood cells, but these have not evolved in populations in the Andes.
Dr Gardner delivered a great lecture, hitting the audience with a lot of technical terms but remaining accessible. I, personally, found the tying together of blue light sensors and hypoxia sensors very enlightening... it all comes down to proteins, and I find the use of similar 'toolkits' to solve different problems to be elegant. He threw in enough humor to keep the lecture from bogging down in the details. It helped, though, to be familiar with terms such as 'kinase' (this is where Secret Science Synergy comes in-the more lectures you go to, the better each one gets. Kudos to Dr Gardner, Margaret and Dorian, and the staff of the beautiful Bell House.
I've been poking around for videos of the good doctor lecturing, but there are a lot of Kevin Gardners, musicians AND biologists, out there. Here is the good doctor speaking at a CUNY open house about his research, starting at the twenty-seven minute mark:
Grab yourself a beverage, check it out, and soak in that SCIENCE!
Showing posts sorted by date for query kinase. Sort by relevance Show all posts
Showing posts sorted by date for query kinase. Sort by relevance Show all posts
Wednesday, January 22, 2020
Wednesday, August 10, 2016
Secret Science Club Post Lecture Recap: Return of a Nobel Winner
Last night, I headed down to the beautiful Bell House, in the Gowanus section of Brooklyn, for this month's Secret Science Club lecture. This month's lecture featured the triumphant return of physiology/medicine Nobel Prize winner and former director of the National Institutes of Health and the National Cancer Institute Dr Harold Varmus, currently with the Meyer Cancer Center at Weill Cornell Medical College, who delivered a lecture on the first anniversary of the Secret Science Club. For the record, this month marks the tenth anniversary of the Secret Science Club. This lecture was one in the continuing collaboration between the Secret Science Club and the Albert and Mary Lasker Foundation
Dr Varmus began his lecture by contrasting the current venue with the original venue of the Secret Science Club, the basement performance space of Park Slope's Union Hall, joking that the Secret Science Club really felt like a secret, something almost revolutionary given the contemporaneous occupant of the White House. He stressed the importance of keeping science in the public domain.
Dr Varmus then presented the basic facts about cancer. Cancer is not one disease, many cell types can give rise to unrestricted cell growth which invades other cells. There are many types of cancer- one wouldn't lump all infectious diseases together, so one shouldn't lump all cancers together. Cancers are illnesses of the genome. Some of the genetic risk factors are relatively minor, but other risk factors are closely related to the illness. Genetic changes occur in an individual's lifetime- DNA can be damaged by such factors as smoking or exposure to ultraviolet light. Small or large, changes to DNA can have dramatic results. Cancers are best described as 'too many cells doing bad things in the wrong places'. Different cancers can effect cells differently- some reduce cell function, while some increase function... all to the detriment of the organism.
Cancers become more frequent with age. The approach to fighting cancers must be multi-pronged. Researchers must observe and count cancers in populations. Screening must be performed- cancers must be diagnosed with specificity early on, and classified. Patients must me treated and comforted. Prevention must be attempted to reduce the incidence of cancer. Cancer must be studied in its various forms.
Dr Varmus displayed several graphs comparing the age-adjusted death rates for cancer and heart disease for individuals under the age of 85. He noted that the death rate for cancers peaked in the 1990s. He noted that the cancer death rates are decreasing, but not as dramatically as the death rate for heart disease. Different cancers have different mortality rates. Lung cancer mortality rates tend to be high, but are precipitously declining. Stomach and colorectal cancers are declining. Among women, there is a rapid decline of uterine cancers due to Pap smears, and the HPV vaccine could improve things further.
The traditional treatment for cancer involves surgery, chemotherapy, and radiotherapy. These therapies are extremely difficult for patients. An improvement in treatment would involve targeted therapies directed toward the genetic anomalies which produce the proteins which cause cancers. Two promising new therapeutic innovations are hormone therapy and immunotherapy. Of course, cancer prevention is preferable to treatment- tobacco use, viruses, obesity, and ultraviolet light exposure are all contributors to increased cancer risk. Vaccines against viruses such as HPV and hepatitis-B would reduce cancer risk. Screenings to recognize genetic predispositions to cancer are also promising.
Dr Varmus then proceeded to frame the discussion of the fight against cancer in historic terms, starting with Richard Nixon's signing of the National Cancer Act of 1971. This act was aspirational without a plan- we did not know how a normal cell becomes a cancer cell. There was a confidence, though, that money plus talent equals results. In the subsequent decades, new concepts, new methods, and new strategies emerged- genome research, DNA crystallography, computational methods. This fight culminated in President Obama's 2016 Precision Medicine Initiative. A base of information about diseases' genetic or molecular factors needs to be compiled. Taxonomy leads to better diagnoses, which lead to better treatments, which lead to better outcomes. Vice President Biden was tapped to lead the "moonshot" against cancer- a successful response to this challenge would be more effective, more efficient, and involve more collaboration.
Dr Varmus veered off to a short autobiography- his childhood was spent on Long Island. He studied literature in college though he did plan to attend medical school. After what he described as a 'prolonged adolescence', he became a scientist at the age of twenty-eight. He described the historical facts which influenced his life- hearing Eisenhower's push for scientific excellence, attending medical school while the Vietnam War raged, Nixon's signing of the National Cancer Act in 1971. He described his early days at the NIH as being a member of the 'yellow berets'. He displayed a picture of his 1968 cohort at the NIH and noted the gender imbalance of the organization. While at NIH, he started to study genetic expression in E. coli. He joked, "Few pleasures in life exceed a potent assay." In his case, he was measuring accurately how much RNA was made by a particular gene in E. coli. He noted that to answer complex problems, it was best to use simple models. Clear answers lead to more questions, both mundane and profound. He also noted that the 'gossip factor' was important to scientists- tell results to peers, even competitors, for the advancement of knowledge.
In cancer research, one must apply molecular models to complex organisms in order to determine when a normal cell becomes a violent miscreant which can kill the individual to which it belongs. The few genes in a virus which causes tumors in animals can change the behavior of an animal's cells permanently. How do these genes replicate? How do they cause cancers? How does one tiny retrovirus become thousands of particles? To answer these questions, Dr Varmus recounted the history of Peyton Rous and his researches into chicken tumors. Peyton Rouse, of the Rockefeller Institute (now Rockefeller University) described a transmissible chicken sarcoma in 1910. The sarcoma was caused by a virus which could change the behavior of cells in a petri dish- these 'rounded' cells looked different from the background cells in the dish.
Dr Warmus followed up on this area of inquiry with his collaborator and co-Nobel prize winner J. Michael Bishop. Displaying a sequence of photos of the pair, Dr Warmus joked, "The pictures show the changes in our own morphology over time." Dr Warmus and Dr Bishop's best known discovery was proto-oncogenes. In one instance, the tumor causing retroviral gene v-SRC is similar to, and derived from a cellular gene c-SRC. Genes code for enzymes, and genes with mutations cause cellular changes. Using a molecular probe, a nuclear-coded set of amino acids, it was determined that normal chickens have a set of genes which resemble viral genomes, a code for proteins similar to genes present in all metazoans, which suggests an important function. The discovery of c-SRC was important for being 'ahead of its time', there was no genetic sequencing at the time. The discovery also reversed existing thought- the normal gene was similar to the cancer gene. There were also evolutionary implications- evolution occurs through the same sort of changes which can result in cancers. Extensibility also comes into play, there are parallel cases of viral genes which are derived from cellular genes. Another factor is the functionality of the proto-oncogene, which encodes a novel enzyme, a tyrosine-protein kinase (the role of kinases in cancers was the subject of the June 2014 lecture by Dr Charles Sawywers). Understanding the role of proto-oncogenes in tumor foundation provides targets for therapies. In a particularly elegant symmetry, the discovery of the viral genes was the guide to the proto-oncogenes, and the viral genes are derived from cellular genes. The pattern of research into tumors typically goes as follows: human tumor cells are isolated, DNA from the tumor cells is purified and inserted into mouse cells, and the transformed cells become the focus of further experimentation.
Dr Warmus then brought up the topic of Chronic Myeloid Leukemia. CML typically has an early phase of five years, then a patient will undergo a blast crisis in the sixth year. CML patients typically have a 22/9 chimera, a transposition of genetic material between chromosome 9 and chromosome 22. This proto-oncogene was originally found in mouse tumors- a drug marketed as Gleevec blocks the oncogenic enzyme and kills the cancer cells, resulting in complete remission.
The situation is not always so simple- new studies reveal the complexity of cancer- for every type of cancer, there are ranges of mutational activity. In the case of lung cancers, which kill more than one million individuals annually, there are complex patterns of mutated genes, and heterogenous situations underlying the cancers. In a sizable percentage of lung cancers, it is hard to pin down genetic component, another sizable percentage can be attributed to mutations of the KRAS gene, and the remainder of cases can be attributed to various other driver genes. Even with these various underlying mutations, many drugs can be developed to cope with these cancers. The problem is that the lifespans of drugs are short, while cancers are not static- cancers evolve. In the case of renal cancer, heterogenous tumors can stymie targeted therapies and cancer 'phylogenies' are reminiscent of the evolutionary lineages of species. The evolution of various tumor subclones provides drug resistance to tumors, and increases the probability of metastasis.
Successful treatments must confront cancer's complexity- malignant cell behaviors should be targeted, not just a list of damaged genes and altered proteins. One promising avenue for treatment is harnessing the immune system to rein in or destroy cancer cells. For immunotherapy to 'come of age', targeted antibodies are necessary. Monoclonal antibodies can be developed to target specific antigens on tumor cells. The body's own T-cells can be engineered to target antigens on tumor cells with proteins known as chimeric antigen receptors.
Cancer prevention is of the utmost importance, involving risk assessment and early diagnosis, with liquid biopsies being a promising non-invasive early screening technique.
Dr Warmus ended his lecture with the observation that, in confronting cancer, one must grasp its complexity and seek simple solutions.
The lecture was followed by a Q&A session. The first question involved the origin of sarcomas- sarcomas arise from the mesenchyme, tissues such as fat and bone. Dr Warmus advised us not to mistake the causes of cancer with the mechanisms of cancer- cellular 'damage' may result from inherited genes or from the very process of mitosis. A lot of mutations arise through the process of cell division- the error prone nature of cell division is responsible for evolution as well as cancer. Some bastard in the audience, who had attended Dr Warmus' 2007 lecture, asked him about the changes that had occurred in the interim between the two lectures- which of them were the most significant? Dr Warmus noted that DNA sequencing had become much faster and cheaper in the intervening years. While the number of successes in cancer research have not profoundly changed the 'cancer landscape', a proliferation of small-scale successes has led to optimism about the long-haul. Immunotherapy, a new field, is very promising. Another questioner asked about liquid biopsies- mutations in newly formed tumors can be analyzed using blood samples. Regarding policies to improve cancer treatment, gene therapy reimbursement rates should be improved- genetic tests are not that expensive, and the costs pale in comparison to hospital stays and imaging. The cost of drugs is more difficult to control- different drugs have different success rates, should patients only pay for effective drugs? There is also a detrimental cost of not treating viral infections- novel solutions are required. Another individual asked if stress was a risk factor for cancer. Dr Warmus indicated that it was possible, but not on the level of tobacco use... he then quipped that cell division itself promotes cancer. Dr Warmus then brought up the Cancer Genome Atlas, a collaborative effort by scientists sharing data on the genetics of various cancers. The final question of the night involved antibody checkpoint inhibitors, specifically inhibitors of the PD-L1 protein. Dr Warmus cautioned that these therapies pose dangers- unchecked T-cells could attack normal cells, so this sort of therapy is not to be taken lightly. It's not a long-term therapy but the risk might be worth it on a short-term basis. The danger of using antibody checkpoint inhibitors is that the therapy perturbs a fundamental feature of the immune system.
Once again, the Secret Science Club, in conjunction with the Lasker Foundation and the Bell House staff, served up a fantastic lecture. Kudos to Dr Warmus, Margaret and Dorian, the staff of the beautiful Bell House, and the good people of the Lasker Foundation. Dr Warmus was around for the first anniversary of the SSC, so he was the perfect lecturer for the tenth anniversary.
Here's a video of Dr Warmus delivering a lecture to an audience at Paris' Institut Curie:
Pour yourself a libation, sit back, and soak in that ambience of the Secret Science Club. It's been ten years, ten great years of Learning While Intoxicated. Thanks again to Dorian and Margaret... happy tenth anniversary!
Dr Varmus began his lecture by contrasting the current venue with the original venue of the Secret Science Club, the basement performance space of Park Slope's Union Hall, joking that the Secret Science Club really felt like a secret, something almost revolutionary given the contemporaneous occupant of the White House. He stressed the importance of keeping science in the public domain.
Dr Varmus then presented the basic facts about cancer. Cancer is not one disease, many cell types can give rise to unrestricted cell growth which invades other cells. There are many types of cancer- one wouldn't lump all infectious diseases together, so one shouldn't lump all cancers together. Cancers are illnesses of the genome. Some of the genetic risk factors are relatively minor, but other risk factors are closely related to the illness. Genetic changes occur in an individual's lifetime- DNA can be damaged by such factors as smoking or exposure to ultraviolet light. Small or large, changes to DNA can have dramatic results. Cancers are best described as 'too many cells doing bad things in the wrong places'. Different cancers can effect cells differently- some reduce cell function, while some increase function... all to the detriment of the organism.
Cancers become more frequent with age. The approach to fighting cancers must be multi-pronged. Researchers must observe and count cancers in populations. Screening must be performed- cancers must be diagnosed with specificity early on, and classified. Patients must me treated and comforted. Prevention must be attempted to reduce the incidence of cancer. Cancer must be studied in its various forms.
Dr Varmus displayed several graphs comparing the age-adjusted death rates for cancer and heart disease for individuals under the age of 85. He noted that the death rate for cancers peaked in the 1990s. He noted that the cancer death rates are decreasing, but not as dramatically as the death rate for heart disease. Different cancers have different mortality rates. Lung cancer mortality rates tend to be high, but are precipitously declining. Stomach and colorectal cancers are declining. Among women, there is a rapid decline of uterine cancers due to Pap smears, and the HPV vaccine could improve things further.
The traditional treatment for cancer involves surgery, chemotherapy, and radiotherapy. These therapies are extremely difficult for patients. An improvement in treatment would involve targeted therapies directed toward the genetic anomalies which produce the proteins which cause cancers. Two promising new therapeutic innovations are hormone therapy and immunotherapy. Of course, cancer prevention is preferable to treatment- tobacco use, viruses, obesity, and ultraviolet light exposure are all contributors to increased cancer risk. Vaccines against viruses such as HPV and hepatitis-B would reduce cancer risk. Screenings to recognize genetic predispositions to cancer are also promising.
Dr Varmus then proceeded to frame the discussion of the fight against cancer in historic terms, starting with Richard Nixon's signing of the National Cancer Act of 1971. This act was aspirational without a plan- we did not know how a normal cell becomes a cancer cell. There was a confidence, though, that money plus talent equals results. In the subsequent decades, new concepts, new methods, and new strategies emerged- genome research, DNA crystallography, computational methods. This fight culminated in President Obama's 2016 Precision Medicine Initiative. A base of information about diseases' genetic or molecular factors needs to be compiled. Taxonomy leads to better diagnoses, which lead to better treatments, which lead to better outcomes. Vice President Biden was tapped to lead the "moonshot" against cancer- a successful response to this challenge would be more effective, more efficient, and involve more collaboration.
Dr Varmus veered off to a short autobiography- his childhood was spent on Long Island. He studied literature in college though he did plan to attend medical school. After what he described as a 'prolonged adolescence', he became a scientist at the age of twenty-eight. He described the historical facts which influenced his life- hearing Eisenhower's push for scientific excellence, attending medical school while the Vietnam War raged, Nixon's signing of the National Cancer Act in 1971. He described his early days at the NIH as being a member of the 'yellow berets'. He displayed a picture of his 1968 cohort at the NIH and noted the gender imbalance of the organization. While at NIH, he started to study genetic expression in E. coli. He joked, "Few pleasures in life exceed a potent assay." In his case, he was measuring accurately how much RNA was made by a particular gene in E. coli. He noted that to answer complex problems, it was best to use simple models. Clear answers lead to more questions, both mundane and profound. He also noted that the 'gossip factor' was important to scientists- tell results to peers, even competitors, for the advancement of knowledge.
In cancer research, one must apply molecular models to complex organisms in order to determine when a normal cell becomes a violent miscreant which can kill the individual to which it belongs. The few genes in a virus which causes tumors in animals can change the behavior of an animal's cells permanently. How do these genes replicate? How do they cause cancers? How does one tiny retrovirus become thousands of particles? To answer these questions, Dr Varmus recounted the history of Peyton Rous and his researches into chicken tumors. Peyton Rouse, of the Rockefeller Institute (now Rockefeller University) described a transmissible chicken sarcoma in 1910. The sarcoma was caused by a virus which could change the behavior of cells in a petri dish- these 'rounded' cells looked different from the background cells in the dish.
Dr Warmus followed up on this area of inquiry with his collaborator and co-Nobel prize winner J. Michael Bishop. Displaying a sequence of photos of the pair, Dr Warmus joked, "The pictures show the changes in our own morphology over time." Dr Warmus and Dr Bishop's best known discovery was proto-oncogenes. In one instance, the tumor causing retroviral gene v-SRC is similar to, and derived from a cellular gene c-SRC. Genes code for enzymes, and genes with mutations cause cellular changes. Using a molecular probe, a nuclear-coded set of amino acids, it was determined that normal chickens have a set of genes which resemble viral genomes, a code for proteins similar to genes present in all metazoans, which suggests an important function. The discovery of c-SRC was important for being 'ahead of its time', there was no genetic sequencing at the time. The discovery also reversed existing thought- the normal gene was similar to the cancer gene. There were also evolutionary implications- evolution occurs through the same sort of changes which can result in cancers. Extensibility also comes into play, there are parallel cases of viral genes which are derived from cellular genes. Another factor is the functionality of the proto-oncogene, which encodes a novel enzyme, a tyrosine-protein kinase (the role of kinases in cancers was the subject of the June 2014 lecture by Dr Charles Sawywers). Understanding the role of proto-oncogenes in tumor foundation provides targets for therapies. In a particularly elegant symmetry, the discovery of the viral genes was the guide to the proto-oncogenes, and the viral genes are derived from cellular genes. The pattern of research into tumors typically goes as follows: human tumor cells are isolated, DNA from the tumor cells is purified and inserted into mouse cells, and the transformed cells become the focus of further experimentation.
Dr Warmus then brought up the topic of Chronic Myeloid Leukemia. CML typically has an early phase of five years, then a patient will undergo a blast crisis in the sixth year. CML patients typically have a 22/9 chimera, a transposition of genetic material between chromosome 9 and chromosome 22. This proto-oncogene was originally found in mouse tumors- a drug marketed as Gleevec blocks the oncogenic enzyme and kills the cancer cells, resulting in complete remission.
The situation is not always so simple- new studies reveal the complexity of cancer- for every type of cancer, there are ranges of mutational activity. In the case of lung cancers, which kill more than one million individuals annually, there are complex patterns of mutated genes, and heterogenous situations underlying the cancers. In a sizable percentage of lung cancers, it is hard to pin down genetic component, another sizable percentage can be attributed to mutations of the KRAS gene, and the remainder of cases can be attributed to various other driver genes. Even with these various underlying mutations, many drugs can be developed to cope with these cancers. The problem is that the lifespans of drugs are short, while cancers are not static- cancers evolve. In the case of renal cancer, heterogenous tumors can stymie targeted therapies and cancer 'phylogenies' are reminiscent of the evolutionary lineages of species. The evolution of various tumor subclones provides drug resistance to tumors, and increases the probability of metastasis.
Successful treatments must confront cancer's complexity- malignant cell behaviors should be targeted, not just a list of damaged genes and altered proteins. One promising avenue for treatment is harnessing the immune system to rein in or destroy cancer cells. For immunotherapy to 'come of age', targeted antibodies are necessary. Monoclonal antibodies can be developed to target specific antigens on tumor cells. The body's own T-cells can be engineered to target antigens on tumor cells with proteins known as chimeric antigen receptors.
Cancer prevention is of the utmost importance, involving risk assessment and early diagnosis, with liquid biopsies being a promising non-invasive early screening technique.
Dr Warmus ended his lecture with the observation that, in confronting cancer, one must grasp its complexity and seek simple solutions.
The lecture was followed by a Q&A session. The first question involved the origin of sarcomas- sarcomas arise from the mesenchyme, tissues such as fat and bone. Dr Warmus advised us not to mistake the causes of cancer with the mechanisms of cancer- cellular 'damage' may result from inherited genes or from the very process of mitosis. A lot of mutations arise through the process of cell division- the error prone nature of cell division is responsible for evolution as well as cancer. Some bastard in the audience, who had attended Dr Warmus' 2007 lecture, asked him about the changes that had occurred in the interim between the two lectures- which of them were the most significant? Dr Warmus noted that DNA sequencing had become much faster and cheaper in the intervening years. While the number of successes in cancer research have not profoundly changed the 'cancer landscape', a proliferation of small-scale successes has led to optimism about the long-haul. Immunotherapy, a new field, is very promising. Another questioner asked about liquid biopsies- mutations in newly formed tumors can be analyzed using blood samples. Regarding policies to improve cancer treatment, gene therapy reimbursement rates should be improved- genetic tests are not that expensive, and the costs pale in comparison to hospital stays and imaging. The cost of drugs is more difficult to control- different drugs have different success rates, should patients only pay for effective drugs? There is also a detrimental cost of not treating viral infections- novel solutions are required. Another individual asked if stress was a risk factor for cancer. Dr Warmus indicated that it was possible, but not on the level of tobacco use... he then quipped that cell division itself promotes cancer. Dr Warmus then brought up the Cancer Genome Atlas, a collaborative effort by scientists sharing data on the genetics of various cancers. The final question of the night involved antibody checkpoint inhibitors, specifically inhibitors of the PD-L1 protein. Dr Warmus cautioned that these therapies pose dangers- unchecked T-cells could attack normal cells, so this sort of therapy is not to be taken lightly. It's not a long-term therapy but the risk might be worth it on a short-term basis. The danger of using antibody checkpoint inhibitors is that the therapy perturbs a fundamental feature of the immune system.
Once again, the Secret Science Club, in conjunction with the Lasker Foundation and the Bell House staff, served up a fantastic lecture. Kudos to Dr Warmus, Margaret and Dorian, the staff of the beautiful Bell House, and the good people of the Lasker Foundation. Dr Warmus was around for the first anniversary of the SSC, so he was the perfect lecturer for the tenth anniversary.
Here's a video of Dr Warmus delivering a lecture to an audience at Paris' Institut Curie:
Pour yourself a libation, sit back, and soak in that ambience of the Secret Science Club. It's been ten years, ten great years of Learning While Intoxicated. Thanks again to Dorian and Margaret... happy tenth anniversary!
Wednesday, June 11, 2014
Secret Science Club Post Lecture Recap: Targeting Tumors
Last night, I headed down to the beautiful Bell House in the Gowanus section of Brooklyn for this month's Secret Science Club lecture. Last night's lecture, a collaboration between the Secret Science Club and Lasker Foundation, featured Dr Charles Sawyers, whose C.V. is most prestigious... cutting and pasting from the SSC blog post, he's "chair of the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center, investigator at the Howard Hughes Medical Institute, and professor in the Cell and Developmental Biology Program and Department of Medicine at the Weill Cornell Graduate School of Medical Sciences". Wow, the man is affiliated with some incredible institutions... poking around the t00bz, I also discovered that he is president of the American Association for Cancer Research.
The topic of the lecture was cancer treatment using "targeted" medicines. Dr Sawyers began the talk with a rueful mention of the inadequacy of funding for medical research. He followed this clarion call for better funding with a basic definition of cancer- cancer involves the development of tumors, which are abnormal growths of tissue. A benign tumor is a non-invasive mass, while a malignant tumor "invades" surrounding tissue. Metastatic tumors have infiltrated numerous tissues throughout the body. Traditionally, tumors were treated using surgery, radiation, chemotherapy, or a combination of the three. Dr Sawyers stated that a new approach was needed to treat cancer, a targeted approach.
Cancer is caused by mutations in the host's DNA- these mutations can be inherited or due to environmental conditions (such as carcinogens present in tobacco smoke or overexposure to the sun's UV rays). Oncogenes are genes which can potentially result in cancer, while suppressive genes act against tumor formation. Proto-oncogenes are involved in normal development, but can mutate to form an oncogene, which will result in cancerous growth. Suppressive genes stop cell growth, but can malfunction- a lack of suppressors will cause tumor growth.
As an example of the role of genes in cancer, Dr Sawyers cited the example of chronic myeloid leukemia, a blood cancer which causes an overproduction of white blood cells. Chronic myeloid leukemia involves a genetic transposition called the Philadelphia chromosome- researchers noticed that chromosome 22 in CML patients was stubby, while chromosome 9 was elongated- in the tumor cells there was a reciprocal translocation of genetic material between chromosome 22 and chromosome 9, shortening 22 and lengthening 9. The particular gene translocated is the Abl gene, which becomes fused with the BCR gene on the 22nd chromosome. The BCR-ABL fusion results in a kinase which binds ATP with a substrate, causing a chain reaction that results in abnormal growth. Dr Sawyer not only had a sweet animation of ATP engaging with the kinase, but had two models of the kinase that ended up on the bar by the end of the lecture (they were eventually returned to him, along with a nice IPA). A drug, marketed as Gleevec, was formulated to "jam" the active loop between the ATP and the kinase in order to stop abnormal white blood cell growth- the drug mimics ATP, but lacks the phosphate group that binds with the kinase, resulting in a reduced white blood cell count within thirty days.
Tumor cells can develop a resistance to drugs such as Gleevec, resulting in a relapse. A one nucleotide difference in a gene can prevent the ATP binding which stops the abnormal cell growth. The binding problem is solvable using new drugs that will work when the cancerous cells evolve resistance. There are over 500 kinases which bind ATP, and Gleevec can bind three of them- specific drugs are needed to bind specific kinases. As gene sequencing becomes more rapid, and less expensive, targeted therapy has improved, and implementation is more rapid. Since cancer is caused by mutation, efforts are underway to sequence the genetics of all cancers- new technology has reduced the cost of genetic sequencing to about $3,000, so tumors are now sequenced routinely. Once sequencing takes place, the DNA of cancerous cells is compared to that of healthy cells and "silent mutations" are filtered out. Once a database is created, the number of mutations in a tumor can be determined. There is a vast difference between the number of mutations in pediatric tumors, which can have a nucleotide "mistake" rate as low as one in a billion, and adult tumors, which average 50-100 mutations.
One ongoing project is determining where mutations occur, and compiling a "data map" of cancer genes. Currently, there are 140 "mapped" cancer genes, with 200 being the projected number of cancer genes. Out of the 140 known cancer genes, 60 are dominant and 80 are recessive. These genes regulate cell growth, cell fate and cell death (for example, malfunctions of the epidermal growth factor can result in unregulated cell division- Dr Sawyer illustrated this with an animation of out-of control cell growth among intestinal villi). In normal growth, undifferentiated stem cells can differentiate into progenitor cells, which can only differentiate further into a specific "final cell". In the course of the normal cell cycle, cell death eventually occurs.
In the case of cancers involving a malfunction of the Epithelial Growth Factor, the drug Erlotinib, another kinase inhibitor, was developed to block the growth signalling pathway. Targeted therapy has grown rapidly in the past decade and a half, with thirty-seven drugs being developed between 2001 and 2013. The therapeutic goal is to have three drugs per tumor gene, in order to counteract the development of drug resistance.
The key to developing targeted therapies is better cancer taxonomy. Put simply, knowledge makes treatment more successful. Dr Sawyer indicated that immunotherapy- harnessing the body's immune system to fight tumor cells, is a promising area of future inquiry.
In the Q&A session, some so-and-so asked the question that the Bastard was planning on asking, concerning the role of viruses in human cancers. Dr Sawyer implicated three viruses in cancers- the human papillomaviruses, Hepatitis B, and Hepatitis C. While formulating another question, the Bastard received a job-related phone call and had to go to his field office (the men's loo, natch) to answer the call.
Here is a video of Dr Sawyer giving a similar lecture on CML and targeted therapy (note the sweet ABL-BCR animation at around 3:15):
He looks kinda thirsty in that video... he didn't have that problem at the Bell House.
Once again, the Secret Science Club has delivered a top-notch lecture. In this case, the SSC and the Lasker Foundation were able to combine in a synergistic effect, powerful enough to overcome even the most resistant ignorance.
Special thanks to Dorian, Margaret, Dr Sawyer, and the staff of the beautiful Bell House... again!
The topic of the lecture was cancer treatment using "targeted" medicines. Dr Sawyers began the talk with a rueful mention of the inadequacy of funding for medical research. He followed this clarion call for better funding with a basic definition of cancer- cancer involves the development of tumors, which are abnormal growths of tissue. A benign tumor is a non-invasive mass, while a malignant tumor "invades" surrounding tissue. Metastatic tumors have infiltrated numerous tissues throughout the body. Traditionally, tumors were treated using surgery, radiation, chemotherapy, or a combination of the three. Dr Sawyers stated that a new approach was needed to treat cancer, a targeted approach.
Cancer is caused by mutations in the host's DNA- these mutations can be inherited or due to environmental conditions (such as carcinogens present in tobacco smoke or overexposure to the sun's UV rays). Oncogenes are genes which can potentially result in cancer, while suppressive genes act against tumor formation. Proto-oncogenes are involved in normal development, but can mutate to form an oncogene, which will result in cancerous growth. Suppressive genes stop cell growth, but can malfunction- a lack of suppressors will cause tumor growth.
As an example of the role of genes in cancer, Dr Sawyers cited the example of chronic myeloid leukemia, a blood cancer which causes an overproduction of white blood cells. Chronic myeloid leukemia involves a genetic transposition called the Philadelphia chromosome- researchers noticed that chromosome 22 in CML patients was stubby, while chromosome 9 was elongated- in the tumor cells there was a reciprocal translocation of genetic material between chromosome 22 and chromosome 9, shortening 22 and lengthening 9. The particular gene translocated is the Abl gene, which becomes fused with the BCR gene on the 22nd chromosome. The BCR-ABL fusion results in a kinase which binds ATP with a substrate, causing a chain reaction that results in abnormal growth. Dr Sawyer not only had a sweet animation of ATP engaging with the kinase, but had two models of the kinase that ended up on the bar by the end of the lecture (they were eventually returned to him, along with a nice IPA). A drug, marketed as Gleevec, was formulated to "jam" the active loop between the ATP and the kinase in order to stop abnormal white blood cell growth- the drug mimics ATP, but lacks the phosphate group that binds with the kinase, resulting in a reduced white blood cell count within thirty days.
Tumor cells can develop a resistance to drugs such as Gleevec, resulting in a relapse. A one nucleotide difference in a gene can prevent the ATP binding which stops the abnormal cell growth. The binding problem is solvable using new drugs that will work when the cancerous cells evolve resistance. There are over 500 kinases which bind ATP, and Gleevec can bind three of them- specific drugs are needed to bind specific kinases. As gene sequencing becomes more rapid, and less expensive, targeted therapy has improved, and implementation is more rapid. Since cancer is caused by mutation, efforts are underway to sequence the genetics of all cancers- new technology has reduced the cost of genetic sequencing to about $3,000, so tumors are now sequenced routinely. Once sequencing takes place, the DNA of cancerous cells is compared to that of healthy cells and "silent mutations" are filtered out. Once a database is created, the number of mutations in a tumor can be determined. There is a vast difference between the number of mutations in pediatric tumors, which can have a nucleotide "mistake" rate as low as one in a billion, and adult tumors, which average 50-100 mutations.
One ongoing project is determining where mutations occur, and compiling a "data map" of cancer genes. Currently, there are 140 "mapped" cancer genes, with 200 being the projected number of cancer genes. Out of the 140 known cancer genes, 60 are dominant and 80 are recessive. These genes regulate cell growth, cell fate and cell death (for example, malfunctions of the epidermal growth factor can result in unregulated cell division- Dr Sawyer illustrated this with an animation of out-of control cell growth among intestinal villi). In normal growth, undifferentiated stem cells can differentiate into progenitor cells, which can only differentiate further into a specific "final cell". In the course of the normal cell cycle, cell death eventually occurs.
In the case of cancers involving a malfunction of the Epithelial Growth Factor, the drug Erlotinib, another kinase inhibitor, was developed to block the growth signalling pathway. Targeted therapy has grown rapidly in the past decade and a half, with thirty-seven drugs being developed between 2001 and 2013. The therapeutic goal is to have three drugs per tumor gene, in order to counteract the development of drug resistance.
The key to developing targeted therapies is better cancer taxonomy. Put simply, knowledge makes treatment more successful. Dr Sawyer indicated that immunotherapy- harnessing the body's immune system to fight tumor cells, is a promising area of future inquiry.
In the Q&A session, some so-and-so asked the question that the Bastard was planning on asking, concerning the role of viruses in human cancers. Dr Sawyer implicated three viruses in cancers- the human papillomaviruses, Hepatitis B, and Hepatitis C. While formulating another question, the Bastard received a job-related phone call and had to go to his field office (the men's loo, natch) to answer the call.
Here is a video of Dr Sawyer giving a similar lecture on CML and targeted therapy (note the sweet ABL-BCR animation at around 3:15):
He looks kinda thirsty in that video... he didn't have that problem at the Bell House.
Once again, the Secret Science Club has delivered a top-notch lecture. In this case, the SSC and the Lasker Foundation were able to combine in a synergistic effect, powerful enough to overcome even the most resistant ignorance.
Special thanks to Dorian, Margaret, Dr Sawyer, and the staff of the beautiful Bell House... again!
Thursday, March 14, 2013
Post Lecture Recap: This One is Memorable!
On Tuesday night, I headed down to the beautiful Bell House in the Gowanus section of Brooklyn, for the latest Secret Science Club lecture, by NYU neurobiologist and biomedical engineer André Fenton, who studies the "mechanics" of memory. Besides his academic endeavors, Dr Fenton started the Biosignal Group, which produces a miniature, wireless EEG monitor.
Dr Fenton started his lecture with a quote by Gautama Siddhartha: "All that we are is the result of what we have thought. What we think, we become."
Memory is characterized by "truthiness", memories have a certain "fuzziness" about them. Memory doesn't function like a recording device, it is a reconstructive process, not a reproductive process. Basically, we make up stories... memories are created out of what we expect of the world, not necessarily what happened. We even remember events that never happened. Dr Fenton illustrated this with a memory test in which words such as "bed", "slumber", and "wake" were flashed briefly on a screen, and the audience was quizzed afterword about which words had appeared in the test. A good portion of the audience misremembers the word "sleep" as having appeared, while a word such as "horse" is not falsely remembered.
After this brief illustration of the nature of memory, the talk proceeded to the biology of memory- how does memory work in the brain, and where in the brain should we start to look? The best estimate is that the human brain contains about 100 billion neurons. Each neuron is a "chemical factory" and the interaction of these chemicals have electrophysiological effects. The brain is an electrical organ, neurons send electrochemical signals. To illustrate the connection between neurons, and the role that synapses play in the formation of memory, Dr Fenton showed us a film of the firing of a single entorhinal neuron in the brain of an epilepsy patient who had had electrodes implanted into his brain as a therapeutic measure. The patient was shown various images, and this particular neuron was most active while the patient was shown "Simpsons" clips and while recollecting said "Simpsons" clips. It would seem that single neurons are tuned to particular features of the outside world.
As an example of such "tuning", Dr Fenton cited head direction cells, discovered in Brooklyn, which activate when a rat's head is facing in a particular direction. As another example, place cells activate when a subject is in a particular location. It's important to note that there are no sense organs for place or orientation, so a calculation must be made. Dr Fenton compared this process to a whole "symphony" of cells being active in sense of place, movement, and orientation. The business, and joy, of neuroscience is figuring out how this symphony works.
Dr Fenton then moved on to the topic of synapses, the contacts between neurons- synaptic connections are the fundamental property of neurons. Cognitive experiences leave a lasting imprint within synapses. Experience and other electrochemical relationships "tune" synapses, they set synaptic relationships and maintain them. As Guatama Siddhartha put it, experiences define who you are and who you are going to be.
In studying the anatomy of the brain, experiments on humans is unethical (again, the subject in the aforementioned "single neuron" experiment had had electrodes implanted for therapeutic reasons related to a severe case of epilepsy). As an aside, these ethical standards may be different in the antipodes. Rats and mice are the typical subjects in brain anatomy studies.
Anatomically, the region of the bain most involved in memory is the hippocampus. In the hippocampus, neurons form circuits for information flow and transformation. In an aside, Dr Fenton imparted to us an important life lesson: TRY NOT TO DAMAGE YOUR HIPPOCAMPUS. Dr Fenton then showed us an image of the hippocampus of a mouse which had been genetically engineered so that the neurons produced a protein which made them glow green when active, the image was similar to this. Images of the signals across the synapses shows the organization in the synapses. Information is created, organized, and stored in the synapses as far as we understand. As far as the long-term retention of information, changes occur in the strength of relationships between synapses. Dr Fenton expressed this in a simple, cute and (importantly) memorable fashion: Neurons that fire together wire together.
The next topic was the brain's ability to change despite the limitations of anatomy. Changes in brain activity are dependent on synaptic plasticity. Coincident activation changes synapses- if enough of a chemical is released in a reliable way, subsequent activation is easier.
In a droll aside, Dr Fention informed that audience that "stimulates" is a fancy word for "electrocutes"- stimulating neurons electrically creates a response and rapid stimulation makes the response bigger. Change is important and can be regulated, high frequency stimulation makes a response bigger, and the response remains bigger because of brain changes.
One particular chemical which plays a role in memory is protein kinase M zeta. For more information on PKM zeta, Ed Yong has several relevant blog posts. Experiments demonstrated that the actions of protein kinase M zeta could be inhibited through the use of another protein, zeta inhibitory peptide. Zeta inhibitory peptide undoes the strengthening of synapse sets, in effect resetting the relationship to a "baseline" level. Injecting zeta inhibitory peptide into rats makes even "educated" rats act as if they were naive- in effect, it "erases" memory. Dr Fenton noted that memory is not everything, how one uses memory is also important (I sure hope that using memory to blog about lectures on memory is a worthy use of memory).
Inquiries into how cognitive experience changes the brain involve such questions as: Where is the PKM zeta molecule made? Where does it go? Where in the brain is PKM zeta present? Mice are used as the subjects in theser experiments because their genome is better known and more easily manipulated than that of rats. Trained mice have more PKM zeta present in their brains than untrained mice, and the difference in how much PKM zeta is present in different synapses makes the organization of these synapses apparent. The functional changes are not only due to the fact that the protein is present, but also due to the fact that it changes the synapses- measurement of electrical activity in the brain shows that trained animals produce different signals than animals in an untrained control group. These differences are attributed solely to prior experience. One finding that could have potential therapeutic use is that the manipulation of experience made changes can mitigate brain damage.
Preemptive cognitive experience has the power to change brain and psychological function. To illustrate this, Dr Fenton showed us Sandro Del-Prete's Message d'Amour des Dauphins:
Experience determines how one interprets the world- while it may take a while for you dirty dogs to see the dolphins in the image, a five year old would probably spot them immediately.
The lecture then moved on to possible therapeutic implications of training. Cognitive control is the ability to coordinate the use of information from multiple sources, typically for optimizing actions. Mental illness impairs cognitive control, the basic challenge in psychiatry is to improve cognitive control in patients. Optimal outcomes depend on context, a determination must me made of which information is most relevant in any situation. To illustrate this, Dr Fenton subjected the audience to a Stroop test:
A Stroop test was developed for rats and it was determined that brain-damaged rats had difficulty with the test. The brains of the rats were lesioned in such a way as to mimic schizophrenia, which may be triggered by fetal trauma. The schizophrenic rats had problems recognizing the incongruent stimuli presented in the Stroop test. Cognitive training during adolescence was able to prevent these deficits... early cognitive training may be able to mitigate brain damage. The adolescent cognitive experience prevented the adult cognitive control deficit despite persistent brain damage- the syanpses were "tuned" by training. Early cognitive experience promotes normal brain function- a normal brain is well synchronized, and early cognitive training makes synchronization easier and promotes plasticity. Experience tunes the synaptic communication pathways that create and control information flow through the brain. Cognitive experience in adolescence may be the "therapeutic window" to manipulate the brain in order to mitigate damage.
Dr Fenton then briefly discussed the ethics of prophylactic measures- while he was dubious about the ethics of prophylactic medication, he indicated that cognitive behavioral therapy would be a better therapeutic technique. The inability to focus mentally is debilitating, and cognitive training can mitigate this problem.
In the Q&A, some bastard in the audience was going to ask Dr Fenton if there were different biological mechanisms for short and long-term memory, but some evil mother pre-empted him (just kidding, no offense- the bastard had a sore throat anyway, so he wasn't prepared to bellow anyway). Dr Fenton answered that there was no evidence that different processes were involved.
Once again, the Secret Science Club dished out a, heh heh, memorable lecture. This particular lecture hit that sweet spot at the intersection of hard science, human interest, and social relevance. Bravo SSC and Dr Fenton! For a taste of this lecture, here is a "Studio 360" presentation by Dr André Fenton:
If you pour yourself a drink before hitting play, you'll have some approximation of the awesome power of the Secret Science Club.
Dr Fenton started his lecture with a quote by Gautama Siddhartha: "All that we are is the result of what we have thought. What we think, we become."
Memory is characterized by "truthiness", memories have a certain "fuzziness" about them. Memory doesn't function like a recording device, it is a reconstructive process, not a reproductive process. Basically, we make up stories... memories are created out of what we expect of the world, not necessarily what happened. We even remember events that never happened. Dr Fenton illustrated this with a memory test in which words such as "bed", "slumber", and "wake" were flashed briefly on a screen, and the audience was quizzed afterword about which words had appeared in the test. A good portion of the audience misremembers the word "sleep" as having appeared, while a word such as "horse" is not falsely remembered.
After this brief illustration of the nature of memory, the talk proceeded to the biology of memory- how does memory work in the brain, and where in the brain should we start to look? The best estimate is that the human brain contains about 100 billion neurons. Each neuron is a "chemical factory" and the interaction of these chemicals have electrophysiological effects. The brain is an electrical organ, neurons send electrochemical signals. To illustrate the connection between neurons, and the role that synapses play in the formation of memory, Dr Fenton showed us a film of the firing of a single entorhinal neuron in the brain of an epilepsy patient who had had electrodes implanted into his brain as a therapeutic measure. The patient was shown various images, and this particular neuron was most active while the patient was shown "Simpsons" clips and while recollecting said "Simpsons" clips. It would seem that single neurons are tuned to particular features of the outside world.
As an example of such "tuning", Dr Fenton cited head direction cells, discovered in Brooklyn, which activate when a rat's head is facing in a particular direction. As another example, place cells activate when a subject is in a particular location. It's important to note that there are no sense organs for place or orientation, so a calculation must be made. Dr Fenton compared this process to a whole "symphony" of cells being active in sense of place, movement, and orientation. The business, and joy, of neuroscience is figuring out how this symphony works.
Dr Fenton then moved on to the topic of synapses, the contacts between neurons- synaptic connections are the fundamental property of neurons. Cognitive experiences leave a lasting imprint within synapses. Experience and other electrochemical relationships "tune" synapses, they set synaptic relationships and maintain them. As Guatama Siddhartha put it, experiences define who you are and who you are going to be.
In studying the anatomy of the brain, experiments on humans is unethical (again, the subject in the aforementioned "single neuron" experiment had had electrodes implanted for therapeutic reasons related to a severe case of epilepsy). As an aside, these ethical standards may be different in the antipodes. Rats and mice are the typical subjects in brain anatomy studies.
Anatomically, the region of the bain most involved in memory is the hippocampus. In the hippocampus, neurons form circuits for information flow and transformation. In an aside, Dr Fenton imparted to us an important life lesson: TRY NOT TO DAMAGE YOUR HIPPOCAMPUS. Dr Fenton then showed us an image of the hippocampus of a mouse which had been genetically engineered so that the neurons produced a protein which made them glow green when active, the image was similar to this. Images of the signals across the synapses shows the organization in the synapses. Information is created, organized, and stored in the synapses as far as we understand. As far as the long-term retention of information, changes occur in the strength of relationships between synapses. Dr Fenton expressed this in a simple, cute and (importantly) memorable fashion: Neurons that fire together wire together.
The next topic was the brain's ability to change despite the limitations of anatomy. Changes in brain activity are dependent on synaptic plasticity. Coincident activation changes synapses- if enough of a chemical is released in a reliable way, subsequent activation is easier.
In a droll aside, Dr Fention informed that audience that "stimulates" is a fancy word for "electrocutes"- stimulating neurons electrically creates a response and rapid stimulation makes the response bigger. Change is important and can be regulated, high frequency stimulation makes a response bigger, and the response remains bigger because of brain changes.
One particular chemical which plays a role in memory is protein kinase M zeta. For more information on PKM zeta, Ed Yong has several relevant blog posts. Experiments demonstrated that the actions of protein kinase M zeta could be inhibited through the use of another protein, zeta inhibitory peptide. Zeta inhibitory peptide undoes the strengthening of synapse sets, in effect resetting the relationship to a "baseline" level. Injecting zeta inhibitory peptide into rats makes even "educated" rats act as if they were naive- in effect, it "erases" memory. Dr Fenton noted that memory is not everything, how one uses memory is also important (I sure hope that using memory to blog about lectures on memory is a worthy use of memory).
Inquiries into how cognitive experience changes the brain involve such questions as: Where is the PKM zeta molecule made? Where does it go? Where in the brain is PKM zeta present? Mice are used as the subjects in theser experiments because their genome is better known and more easily manipulated than that of rats. Trained mice have more PKM zeta present in their brains than untrained mice, and the difference in how much PKM zeta is present in different synapses makes the organization of these synapses apparent. The functional changes are not only due to the fact that the protein is present, but also due to the fact that it changes the synapses- measurement of electrical activity in the brain shows that trained animals produce different signals than animals in an untrained control group. These differences are attributed solely to prior experience. One finding that could have potential therapeutic use is that the manipulation of experience made changes can mitigate brain damage.
Preemptive cognitive experience has the power to change brain and psychological function. To illustrate this, Dr Fenton showed us Sandro Del-Prete's Message d'Amour des Dauphins:
Experience determines how one interprets the world- while it may take a while for you dirty dogs to see the dolphins in the image, a five year old would probably spot them immediately.
The lecture then moved on to possible therapeutic implications of training. Cognitive control is the ability to coordinate the use of information from multiple sources, typically for optimizing actions. Mental illness impairs cognitive control, the basic challenge in psychiatry is to improve cognitive control in patients. Optimal outcomes depend on context, a determination must me made of which information is most relevant in any situation. To illustrate this, Dr Fenton subjected the audience to a Stroop test:
A Stroop test was developed for rats and it was determined that brain-damaged rats had difficulty with the test. The brains of the rats were lesioned in such a way as to mimic schizophrenia, which may be triggered by fetal trauma. The schizophrenic rats had problems recognizing the incongruent stimuli presented in the Stroop test. Cognitive training during adolescence was able to prevent these deficits... early cognitive training may be able to mitigate brain damage. The adolescent cognitive experience prevented the adult cognitive control deficit despite persistent brain damage- the syanpses were "tuned" by training. Early cognitive experience promotes normal brain function- a normal brain is well synchronized, and early cognitive training makes synchronization easier and promotes plasticity. Experience tunes the synaptic communication pathways that create and control information flow through the brain. Cognitive experience in adolescence may be the "therapeutic window" to manipulate the brain in order to mitigate damage.
Dr Fenton then briefly discussed the ethics of prophylactic measures- while he was dubious about the ethics of prophylactic medication, he indicated that cognitive behavioral therapy would be a better therapeutic technique. The inability to focus mentally is debilitating, and cognitive training can mitigate this problem.
In the Q&A, some bastard in the audience was going to ask Dr Fenton if there were different biological mechanisms for short and long-term memory, but some evil mother pre-empted him (just kidding, no offense- the bastard had a sore throat anyway, so he wasn't prepared to bellow anyway). Dr Fenton answered that there was no evidence that different processes were involved.
Once again, the Secret Science Club dished out a, heh heh, memorable lecture. This particular lecture hit that sweet spot at the intersection of hard science, human interest, and social relevance. Bravo SSC and Dr Fenton! For a taste of this lecture, here is a "Studio 360" presentation by Dr André Fenton:
If you pour yourself a drink before hitting play, you'll have some approximation of the awesome power of the Secret Science Club.
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